Efficacy and safety of intramuscular (IM) recombinant <i>Erwinia</i> asparaginase in acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL): The Children’s Oncology Group (COG) AALL1931 study.
Authors: Luke Devon Maese, Mignon L. Loh, L. Mi Rim Choi, Tong Lin, Etsuko Aoki, Michelle Zanette, Shirali Agarwal, Jeffrey Alan Silverman, Lewis B. Silverman, Elizabeth A. Raetz, Rachel E. Rau
Journal: Journal of Clinical Oncology (2022)

7001 Background: The inability to receive L-asparaginase (ASNase) therapy due to hypersensitivity is associated with inferior outcomes in patients with ALL or LBL. JZP458, a recombinant Erwinia-derived ASNase from a Pseudomonas fluorescens expression platform, is approved by the FDA for patients with ALL/LBL who have developed hypersensitivity to E. coli–derived ASNase. Here, we report the efficacy and safety of IM JZP458 from COG AALL1931, a phase 2/3, open-label, multicenter, pharmacokinetic (PK) study. Methods: Eligible patients with ALL/LBL had a grade ≥3 allergic reaction or silent inactivation to a pegylated E. coli–derived ASNase. Each remaining dose of pegylated E. coli–derived ASNase was replaced with 6 doses of IM JZP458 on Monday/Wednesday/Friday (M/W/F) over 2-weeks. Three dosing cohorts were enrolled: Cohort 1a, 25 mg/m 2 M/W/F; Cohort 1b, 37.5 mg/m 2 M/W/F; Cohort 1c, 25 mg/m 2 M/W and 50 mg/m 2 F. Efficacy was assessed by the proportion of patients who achieved the last 72-hour (primary endpoint) or 48-hour (key secondary endpoint) nadir serum asparaginase activity (NSAA) levels ≥0.1 IU/mL in the first treatment course. A population PK (PPK) model was developed based on SAA data from AALL1931 to characterize the PK of JZP458 and to inform dosing decisions. Results: 167 patients were enrolled for IM dosing (Cohort 1a, n = 33; Cohort 1b, n = 83; Cohort 1c, n = 51). The median (range) age was 10 (1, 25) years. The median (range) of JZP458 courses received was 5 (1, 14) for Cohort 1a, 5 (1, 15) for Cohort 1b, and 4 (1, 11) for Cohort 1c. Mean (95% CI) SAA levels (IU/mL) at 72-hour were 0.16 (0.12, 0.19) for Cohort 1a, 0.33 (0.27, 0.39) for Cohort 1b, and 0.47 (0.35, 0.59) for Cohort 1c; and 0.45 (0.37, 0.53), 0.88 (0.76, 1.01), and 0.66 (0.54, 0.77), respectively, at 48-hour. Simulated data from the PPK model matched the observed data well. For Cohort 1c, the proportions of patients (95% CI) achieving NSAA levels ≥0.1 IU/mL at the last 72- and 48-hour in Course 1 were 90% (81%, 98%) and 96% (90%, 100%), respectively, based on observed data; and were 92% (91%, 93%) and 94% (93%, 95%) based on modeled data. The Table shows the rates of treatment-related adverse events (TRAEs; all grades) of interest per cohort. Overall, TRAEs leading to discontinuation included pancreatitis (6%), drug hypersensitivity (4%), anaphylactic reaction (2%), increased alanine aminotransferase (1%), and hyperammonemia (1%). There were no TRAEs leading to death. Conclusions: The totality of the results from AALL1931 demonstrate the positive benefit-risk profile of the IM JZP458 dosing regimen of 25 mg/m 2 M/W and 50 mg/m 2 F with a safety profile consistent with other asparaginases. Clinical trial information: NCT04145531. [Table: see text]